SAN DIEGO, Calif. – The next-generation nonpurine selective xanthine oxidase inhibitor febuxostat, the first new agent for gout in 40 years, proved to be significantly more potent than allopurinol for lowering serum uric acid to <6.0 mg/dL, a level associated with a dissolution of the urate crystals that cause gouty arthritis and a reduction in tophus size, according to new research presented here at the 2005 Annual Meeting of the American College of Rheumatology (ACR).
At the two highest febuxostat doses evaluated, three times as many patients reached the 6.0 mg/dL target urate level compared to patients treated with allopurinol.1
"It appears that febuxostat is a safe and effective treatment for the reduction and elimination of hyperuricemia in patients with gouty arthritis," says Robert Wortmann, MD, professor and chair of rheumatology at the University of Oklahoma in Tulsa. "Febuxostat will prove to be an excellent alternative [to currently available medications], especially for patients who can't tolerate or have allergic reactions to present medications, or for whom the medications we have available have not been effective."
If approved for use in the United States, febuxostat would be the first new medication for gout in more than 40 years, he adds.
The Allopurinol vs Febuxostat in Severe Gout (APEX) study was the longest and largest controlled trial ever conducted in patients with gout. The study involved 1067 patients, who were followed for 28 weeks. The patients were predominantly male, had a mean age of 52 years, and had a variety of comorbidities, including hypertension (47%), hyperlipidemia (33%), cardiovascular disease (13%), obesity (62%), and alcohol use (66%).
The patients were randomly assigned to one of three febuxostat doses (80 mg, 120 mg, or 240 mg/day), to allopurinol 300 mg/day (10 patients received 10 mg/day), or to placebo. The primary efficacy endpoint was the proportion of patients in each group whose last three serum urate measurements were <6.0 mg/dL. Clinical endpoints were the incidence of gout flares requiring treatment between weeks 8 and 28 and the percent reduction in tophi size by physical measurement.
All three doses of febuxostat demonstrated significantly more potent urate-lowering activity compared to allopurinol and placebo. The proportion of patients whose last three urate measurements met the target level was 48% with febuxostat 80 mg, 65% with febuxostat 120 mg, and 69% with febuxostat 240 mg versus 22% with allopurinol (P <.001 for all comparisons). The two higher doses of febuxostat also were superior to the lowest dose (P <.001). Considering only the final urate measurement, the proportion of patients achieving the target level was 76% with febuxostat 80 mg, 87% with febuxostat 120 mg, 94% with febuxostat 240 mg, and 41% with allopurinol.
The incidence of gout flares requiring treatment was similar in the four active-treatment groups. Dr. Wortmann says that patients who reached the target urate level had greater reductions in tophi size compared with patients with higher urate levels, regardless of treatment group.
Adverse event (AE) rates were 16% with allopurinol and 23% with placebo, and ranged between 18% and 29% in the three febuxostat groups. Diarrhea occurred in 7% of patients treated with febuxostat 240 mg. Otherwise, no AE affected more than 4% of patients in any treatment groups. Dr. Wortmann said 34 patients (3%) had serious AEs, only one of which was considered related to study medication (a single elevated serum creatinine level in a patient receiving febuxostat 240 mg).
FACT trial shows reductions in tophus area
The Febuxostat Allopurinol Controlled Trial (FACT),2 also reported at this year's meeting, showed that patients treated for 52 weeks with either 80 mg or 120 mg febuxostat had significantly greater mean reduction in tophus area, compared with 300 mg allopurinol. The results also found that patients with serum urate levels <6.0 mg/dL had a greater reduction in tophus size than those with urate values >e;6.0 mg/dL, thus reaffirming the importance of maintaining subsaturated serum urate levels.
Future studies of febuxostat will include more patients with renal impairment. Because <10% of febuxostat is excreted renally, the drug is thought to be safe for patients with renal impairment, said Dr. Wortmann.
Another study reported at the ACR meeting showed that obesity, hypertension, and use of diuretics have helped fuel a rising incidence of gout among older women.3
Incidence of gout increases substantially in postmenopausal women
The incidence of gout, a male-predominant condition until about age 40, increases substantially in women after menopause, said Hyon Choi, MD, DrPH, an associate professor of medicine at the University of British Columbia in Vancouver.
"According to the Rochester Epidemiologic Project from the Mayo Clinic, the incidence of primary gout has doubled among women over the past 20 years," Dr. Choi says. "Despite the substantial and increasing disease burden among elderly women, no population-based epidemiologic study has investigated risk factors for gout among women."
In an effort to identify risk factors for gout in women, Dr. Choi and colleagues turned to the Nurses Health Study (NHS), a prospective cohort study involving more than 92,000 women. Between 1980 and 2004, 444 new cases of gout were documented in NHS participants.
Analysis of potential clinical and demographic variables associated with gout showed that consumption of low-fat dairy products had a protective effect against gout, consistent with findings in men. Obesity, as reflected by body mass index (BMI), proved to be the most potent risk factor for gout in the NHS women. Compared to women with a BMI <23, those who could be classified as overweight had a 3-fold increased risk of gout. According to World Health Organization obesity criteria, women with a BMI of >e;30 had a 6-fold increased risk of gout, and a BMI of >e;35 conferred a 10-fold increased risk.
Hypertension increased gout risk 4-fold, and use of diuretics was associated with a 5-fold increased risk.
"The same prevention and treatment strategies for these risk factors should be advisable for both men and women," Dr. Choi concludes. "The growing epidemic of obesity and the increased prevalence of hypertension and diuretic use present a substantial challenge to prevention and management of gout. Comprehensive and persistent efforts to modify these risk factors in both sexes could help reduce the incidence of gout and associated morbidities."
References
- Schumacher HR, Becker MA, Wortmann RL, et al. Febuxostat vs allopurinol and placebo in subjects with hyperuricemia and gout: the 28-week APEX study. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1837.
- Wortmann RL, Schumacher HR, Becker MA, et al. Reductions in tophus size in subjects with chronic gout treated with febuxostat or allopurinol for 52 weeks: FACT trial. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 203.
- Choi H, Curhan G. Dairy consumption and risk of incident gout in women: the Nurses Health Study. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 185.